Sweetening the bonds: how O-GlcNAcylation modulates cell adhesion.

Abstract

O-GlcNAcylation is a dynamic, reversible post-translational modification that attaches N-acetylglucosamine (GlcNAc) to the serine or threonine residues of intracellular proteins. Catalysed by O-GlcNAc transferase and removed by O-GlcNAcase, this modification acts as a key nutrient and stress sensor. Although cell adhesion is fundamental to tissue architecture and mechanotransduction, emerging evidence has shown that O-GlcNAcylation profoundly orchestrates these processes. By modulating the composition and signalling of adhesion complexes, O-GlcNAcylation regulates both cell-cell and cell-matrix interactions. Through crosstalk with phosphorylation, this modification drives cellular adhesion plasticity, with broad implications for development, immunity, and diseases, such as cancer and neurodegeneration. Recent advances revealed that O-GlcNAcylation fine-tunes key regulators, including Focal Adhesion Kinase (FAK), Zyxin, and integrins, to control focal adhesion turnover. These mechanistic insights pave the way for novel therapeutic strategies targeting glycosylation-dependent adhesion signalling.